Abstract The adipose-derived secretory factor adiponectin promotes an increase in ceramide catabolism, which is dependent on adiponectin receptors 1 and 2. The receptor-associated ceramidase activity promotes ceramide degradation and generation of sphingosine 1-phosphate (S1P), offering ??cells protection from caspase-8- dependent pro-apoptotic insults. The simple 2-step conversion of ceramide to S1P and starkly opposing roles of the two lipids on cell survival and proliferation has led us and others to postulate the existence of a cellular rheostat governed by these two lipids. As adiponectin promotes improvements in whole body metabolism, it remains unclear whether the local actions of adiponectin within the ??cell elicit these protective effects, or if improvements in the circulating metabolic milieu mediate these protective responses. Understanding this protective mechanism is critical for developing strategies to maintain healthy populations of ?-cells in individuals. I hypothesize that adiponectin receptors promote ?-cell survival and proliferation by governing the ceramide:S1P ratio. Here, I will evaluate the effects of ??cell-specific overexpression of adiponectin receptors or acid ceramidase (a presumed positive control) on the maintenance of functional ??cell mass. Moreover, I will examine the contributions of S1P-mediated protective effects on ?-cell survival in mice lacking S1P receptors (1, 2 or 3) or mice overexpressing the S1P degrading enzyme S1P lyase. To do that, I will take advantage of the ?PANIC-ATTAC? transgenic mouse, which offers inducible, titratable, ??cell specific apoptosis. Since I functionally inactivate the ??cells through mild apoptosis as opposed to necrosis, I reduce the pro-inflammatory component of ??cell death, and thus ??cell mass can be reconstituted upon cessation of dimerizer treatment. Collectively, I will be able to evaluate the effects of adiponectin, adiponectin receptors, acid ceramidase, and S1P on: a) the adiponectin-mediated anti-apoptotic actions in the ?-cell, and b) adiponectin's ability to enhance the regenerative potential of functional ??cell mass. I will also determine if ?-cell-specific overexpression of adiponectin receptor 1, adiponectin receptor 2, or acid ceramidase (AC) is sufficient to maintain functional islet mass using the ob/ob mouse as a model of diabetic ?-cell failure. These studies will hopefully suggest novel therapeutic avenues for the treatment and prevention of diabetes by promoting ?-cell functionality, and by promoting regenerative processes within the ?-cell population.